Analysis of Triplet Motifs in Biological Signed Oriented Graphs Suggests a Relationship Between Fine Topology and Function

Abstract: Background: Networks in different domains are characterized by similar global characteristics while differing in local structures. To further extend this concept, we investigated network regularities on a fine scale in order to examine the functional impact of recurring motifs in signed oriented biological networks. In this work we generalize to signaling net works some considerations made on feedback and feed forward loops and extend them by adding a close scrutiny of Linear Triplets, which have not yet been investigate in detail. Results: We studied the role of triplets, either open or closed (Loops or linear events) by enumerating them in different biological signaling networks and by comparing their significance profiles. We compared different data sources and investigated the fine topology of protein networks representing causal relationships based on transcriptional control, phosphorylation, ubiquitination and binding. Not only were we able to generalize findings that have already been reported but we also highlighted a connection between relative motif abundance and node function. Furthermore, by analyzing for the first time Linear Triplets, we highlighted the relative importance of nodes sitting in specific positions in closed signaling triplets. Finally, we tried to apply machine learning to show that a combination of motifs features can be used to derive node function. Availability: The triplets counter used for this work is available as a Cytoscape App and as a standalone command line Java application. http://apps.cytoscape.org/apps/counttriplets Keywords: Graph theory, graph analysis, graph topology, machine learning, cytoscape